Multiple myeloma (MM) can be a devastating disease causing bone destruction and marrow failure resulting in over ten thousand deaths a year in the USA. It is always preceded by the asymptomatic, premalignant MGUS condition characterized by the expansion of benign clonal plasma cells. This progression to MM is associated with cryptic rearrangements of the MYC locus, which are emerging as the most common genetic abnormality in MM (in over 40% of untreated MM, including 70% of hyperdiploid MM). We hypothesize that these rearrangements can be used to distinguish benign MGUS cells from malignant MM cells. Furthermore, the ability to specifically monitor the eradication of the malignant MM cell (with the MYC rearrangements), while ignoring the residual benign MGUS-type cells (without rearrangements), can maximize the benefit from currently available treatments while keeping toxicities manageable. This hypothesis will be tested by sequencing the MYC rearrangements in matched clinical samples from patients with MM that enter a prolonged MGUS-like state following therapy. We will determine the relative level of rearrangements of the immunoglobulin loci (a measure of all of the clonal PC), and the relative level of the rearrangement of the MYC locus, which we hypothesize, is a measure of the malignant PC. Patients who achieve an MGUS-like state will have no detectable MYC rearrangements, whereas patients with residual malignanat MM cells will have a high probability of having MYC rearrangements in a certain proportion of residual PCs. The second aim is to delve into the basis of this MYC dysregulation. We will identify the specific enhancers interacting with the MYC promoter in a selection of cell lines and characterize these enhancers. The therapeutic response to inhibition of several enhancer-binding proteins will be correlated with specific enhancer structures in both patient samples and cell lines. We will use CRISPR technologies to build isogenic cell lines, differing only in the MYC-linked enhancer, that will enable us to do directed, controlled experiments. Lastly, we will use the Vk*MYC mouse model of MM to determine if tumor burden is reduced upon the genetic ablation of the enhancer driving MYC dysregulation.